Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial.

Objective: Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD).

Design: Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment.

Results: Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=-16); however, there was a significant difference by week 12 (ΔCDAI=-55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed.

Conclusions: A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD.

Trial Registration Number: NCT01203631.